System, method and apparatus for measuring blood flow and blood volume

ABSTRACT

A system for measuring blood flow in an organ of a subject, particularly useful for non-invasive cardiac output monitoring (N.I.C.O.M.™), the system comprises: a radiofrequency generator for generating output radiofrequency signals; a plurality of electrodes, designed to be connectable to the skin of the subject, the electrodes being for transmitting the output radiofrequency signals to the organ and for sensing input radiofrequency signals of the organ. The system further comprises a mixer, electrically communicating with the radiofrequency generator and at least a portion of the plurality of electrodes, for mixing the output radiofrequency signals and the input radiofrequency signals, so as to provide a mixed radiofrequency signal being indicative of the blood flow. The system further comprises electronic circuitry, constructed and designed to filter out a portion of the mixed radiofrequency signal so as to substantially increase a signal-to-noise ratio of a remaining portion of the mixed radiofrequency signal.

RELATED APPLICATIONS

This application is a National Phase Application of PCT Application No.PCT/IL2004/000395 having International Filing Date of May 10, 2004,which claims the benefit of U.S. Provisional Patent Application No.60/469,421, filed on May 12, 2003. The contents of the aboveApplications are all incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to measurement of electrical signals of abody of a subject and, more particularly, to measurement of electricalsignals of the body of the subject so as to determine blood volume orblood volume rate, e.g., stroke volume, cardiac output, brain intraluminal blood volume and the like.

Heart diseases are major causes of morbidity and mortality in the modernworld. Generally, heart diseases may be caused by (i) a failure in theautonomic nerve system where the impulses from the central nervoussystem control to the heart muscle fail to provide a regular heart rateand/or (ii) an insufficient strength of the heart muscle itself whereeven though the patient has a regular heart rate, its force ofcontraction is insufficient. Either way, the amount of blood or the rateat which the blood is supplied by a diseased heart is abnormal and it isappreciated that an assessment of the state of a patient's circulationis of utmost importance.

The simplest measurements, such as heart rate and blood pressure, may beadequate for many patients, but if there is a cardiovascular abnormalitythen more detailed measurements are needed.

Cardiac output (CO) is the volume of blood pumped by the heart during atime interval, which is typically taken to be a minute. Cardiac outputis the product of heart rate (HR) and the amount of blood which ispumped with each heartbeat, also known as the stroke volume (SV). Forexample, the stroke volume at rest in the standing position averagesbetween 60 and 80 ml of blood in most adults. Thus, at a resting heartrate of 80 beats per minute the resting cardiac output varies between4.8 and 6.4 L per min.

A common clinical problem is that of hypotension (low blood pressure);this may occur because the cardiac output is low and/or because of lowsystemic vascular resistance. This problem can occur in a wide range ofpatients, especially those in intensive care or postoperative highdependency units. In these high risk patients, more detailed monitoringis typically established including measuring central venous pressure viaa central venous catheter and continuous display of arterial bloodpressure via a peripheral arterial catheter.

In addition to the above measurements, the measurement of cardiac outputis extremely important For example, when combined with arterial pressuremeasurements, cardiac output can be used for calculating the systemicvascular resistance. The measurement of cardiac output is useful bothfor establishing a patient's initial cardiovascular state and formonitoring the response to various therapeutic interventions such astransfusion, infusion of inotropic drugs, infusion of vasoactive drugs(to increase or reduce systemic vascular resistance) or altering heartrate either pharmacologically or by adjusting pacing rate.

Several methods of measuring cardiac output are presently known. Onesuch method is known as the Fick method, described by Adolf Fick in1870. This method is based on the observation that the amount of oxygenpicked up by the blood as it passes through the lungs is equal to theamount of oxygen taken up by the lungs during breathing. In Fick'smethod, one measures the amount of oxygen taken up by the body duringrespiration and the difference in oxygen concentration between venousand arterial blood and uses these measurements to calculate the amountof blood pumped through the lungs which is equal to the cardiac output.More specifically, in Fick's method the cardiac output equals the ratiobetween the oxygen consumption and the arteriovenous oxygen contentdifference.

Oxygen consumption is typically measured non-invasively at the mouth,while the blood concentrations are measured from mixed venous andperipheral arterial blood drawings. Oxygen consumption is derived bymeasuring the volume of an expired gas over a certain period of time andthe difference in oxygen concentration between the expired gas and theinspired gas.

The Fick method suffers from many drawbacks. First, accurate collectionof the gas is difficult unless the patient has an endotracheal tubebecause of leaks around a facemask or mouthpiece. Second, the analysisof the gas, which is straightforward if the inspired gas is air, isproblematic for oxygen enriched air. Third, the arteriovenous oxygencontent difference presents a further problem in that the mixed venous(i.e., pulmonary arterial) oxygen content has to be measured andtherefore a pulmonary artery catheter is needed to obtain the sample,which may cause complications to the patient.

The Fick principle can also be applied with CO₂ instead of oxygen, bymeasuring CO₂ elimination which can be determined more easily ascompared to oxygen consumption With this variant of Fick's method,cardiac output is proportional to the change in CO₂ elimination dividedby the change in end tidal CO₂ resulting from a brief rebreathingperiod. These changes are accomplished and measured by a sensor, whichperiodically adds a rebreathing volume into the breathing circuitAlthough this method improves the ability to perform accuratemeasurements of gas, it still suffers from most of the abovelimitations, in particular the limitation related to leaks around thefacemask.

Another method is by transoesophageal echocardiography (TOE) whichprovides diagnosis and monitoring of a variety of structural andfunctional abnormalities of the heart. TOE is used to derive cardiacoutput from measurement of blood flow velocity by recording the Dopplershift of ultrasound reflected from the red blood cells. The timevelocity integral, which is the integral of instantaneous blood flowvelocities during one cardiac cycle, is obtained for the blood flow in aspecific site (e.g., the left ventricular outflow tract). The timevelocity integral is multiplied by the cross-sectional area and theheart rate to give cardiac output. Besides being very inaccurate, themethod has the following disadvantages: (i) the system may only beoperated by a skilled operator; (ii) due to the size of the system'sprobe, heavy sedation or anaesthesia is needed; (iii) the system isexpensive; and (iv) the probe cannot be configured to provide continuouscardiac output readings without an expert operator being present.

U.S. Pat. No. 6,485,431 discloses a relatively simple method in whichthe arterial pressure, measured by a pressure cuff or a pressuretonometer, is used for calculating the mean arterial pressure and thetime constant of the arterial system in diastole. The compliance of thearterial system is then determined from a table and used for calculatingthe cardiac output as the product of the mean arterial pressure andcompliance divided by a time constant This method, however, is veryinaccurate and it can only provide a rough estimation of the cardiacoutput.

An additional method of measuring cardiac output is calledthermodilution. This method is based on a principle in which the cardiacoutput can be estimated from the dilution of a bolus of saline being ata different temperature from the blood. The thermodilution involves aninsertion of a fine catheter into a vein, through the heart and into thepulmonary artery. A thermistor, mounted on the tip of the cathetersenses the temperature in the pulmonary artery. A bolus of saline (about5 ml. in volume) is injected rapidly through an opening in the catheter,located in or near to the right atrium of the heart. The saline mixeswith the blood in the heart and temporarily depresses the temperature inthe right atrium. Two temperatures are measured simultaneously the bloodtemperature is measured by the thermistor sensor on the catheter and thetemperature of the saline to be injected is typically measured by meansof a platinum temperature sensor. The cardiac output is inverselyrelated to the area under the curve of temperature depression.

The placement of the catheter into the pulmonary artery is expensive andhas associated risk including: death; infection; hemorrhage;arrhythmias; carotid artery, thoracic duct, vena caval, tracheal, rightatrial, right ventricular, mitral and tricuspid valvular and pulmonaryartery injury. Little evidence suggests that placement of a pulmonaryartery catheter improves survival and several suggest an increase inmorbidity and mortality.

A non-invasive method, known as thoracic electrical bioimpedance, wasfirst disclosed in U.S. Pat. No. 3,340,867 and has recently begun toattract medical and industrial attention [U.S. Pat. Nos. 3,340,867,4,450,527, 4,852,580, 4,870,578, 4,953,556, 5,178,154, 5,309,917,5,316,004, 5,505,209, 5,529,072, 5,503,157, 5,469,859, 5,423,326,5,685,316, 6,485,431, 6,496,732 and 6,511,438; U.S. patent applicationSer. No. 20020193689]. The thoracic electrical bioimpedance method hasthe advantages of providing continuous cardiac output measurement at norisk to the patient.

A typical bioimpedance system includes a tetrapolar array ofcircumferential band electrodes connected to the subject at the base ofthe neck and surrounding the circumference of the lower chest, at thelevel of the xiphoid process. When a constant magnitude alternatingcurrent flows through the upper cervical and lower thoracic bandelectrodes, a voltage, proportional to the thoracic electrical impedance(or reciprocally proportional to the admittance), is measured betweenthe inner cervical and thoracic band electrodes. The portion of thecardiac synchronous impedance change, temporally concordant with thestroke volume, is ascribed solely and uniquely to volume changes of theaorta during expansion and contraction over the heart cycle.

A major disadvantage of existing bioimpedance systems is that thebioimpedance detectors utilized in such systems require severalconsecutive levels of amplifier circuits. Each amplifier circuitundesirably amplifies the input noise from signals detected in a bodysegment, thereby necessitating an increase in the magnitude of themeasurement current to maintain a reasonable signal-to-noise ratio.Multiple amplifier circuits require substantial area on printed circuitboards and utilize numerous circuit components thereby increasing thecost and power consumption of the system. The complexity of multipleamplifier systems decreases the reliability of the systems and increasesthe frequency of required maintenance.

A typical printed circuit board of a bioimpedance system comprises oneor more band pass filters, a half-wave rectification circuit and one ormore low pass filters. One skilled in the art would appreciate that thenoise level is proportional to the bandwidth of the band pass filter. Aspresently available band pass filters are typically characterized by afrequency ratio of about 5%, a considerable portion of the noise passesthe band pass filter hence being folded into the half-wave rectificationcircuit. This problem is aggravated by the fact that the typical changein the impedance within the thorax is about 0.1%, thereby causing arather low signal-to-noise ratio for such systems.

A recognized problem in bioimpedance measurement is the difficulty inseparating and differentiating between cardiovascular bioimpedancesignals and respiratory bioimpedance signals, where the latter aretypically much larger than the former. An optimization method forincreasing the efficiency of the bioimpedance measurement is disclosedin U.S. Pat. No. 4,870,578. In this method, changes in the electricalresistance caused by respiration are suppressed by a clamping circuit,synchronized with the electrical activity of the heart. The clampingcircuit is timed to clamp the voltages in the measuring equipment to abaseline reference voltage in the time preceding the beginning ofmechanical systole. The voltage clamping is released during themechanical systole of the heart so that the changes in the bioimpedancecaused by the pumping action of the heart during mechanical systole aremeasured. Although providing a certain degree of improvement to theefficiency of the measurement, this method still suffers from a ratherlow signal-to-noise ratio.

There is thus a widely recognized need for and it would be highlyadvantageous to have, a system, method and apparatus for measuring bloodflow devoid of the above limitations.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided asystem for measuring blood flow in an organ of a subject, the systemcomprising: a radiofrequency generator for generating outputradiofrequency signals; a plurality of electrodes, designed to beconnectable to the skin of the subject, the electrodes being fortransmitting the output radiofrequency signals to the organ and forsensing input radiofrequency signals of the organ; a mixer, electricallycommunicating with the radiofrequency generator and at least a portionof the plurality of electrodes, for mixing the output radiofrequencysignals and the input radiofrequency signals, so as to provide a mixedradiofrequency signal being indicative of the blood flow; and electroniccircuitry, constructed and designed to filter out a portion of the mixedradiofrequency signal so as to substantially increase a signal-to-noiseratio of a remaining portion of the mixed radiofrequency signal.

According to further features in preferred embodiments of the inventiondescribed below, the system further comprises a data processor forcalculating at least one quantity using the remaining portion of themixed radiofrequency signal, the at least one quantity being selectedfrom the group consisting of a stroke volume, a cardiac output, a brainintra luminal blood flow and an artery blood flow rate.

According to still further features in the described preferredembodiments the system further comprises a pacemaker, communicating withthe data processor and operable to control a heart rate of the subject,wherein the data processor is programmed to electronically control thepacemaker, in accordance with a value of the at least one quantity.

According to still further features in the described preferredembodiments the system further comprises a drug administrating device,communicating with the data processor and operable to administrate drugsto the subject, wherein the data processor is programmed toelectronically control the drug administrating device, in accordancewith a value of the at least one quantity.

According to still further features in the described preferredembodiments the system further comprises a cardiac assist device,communicating with the data processor and operable to increase thecardiac output.

According to still further features in the described preferredembodiments the cardiac assist device comprises a reinforcing memberdesigned and configured to restrict an expansion of a portion of a hearttissue, thereby to increase the cardiac output.

According to still further features in the described preferredembodiments the system further comprises a bioimpedance detectorelectrically communicating with at least a portion of the plurality ofelectrodes for detecting a voltage between a first location and a secondlocation of the subject and for generating the input radiofrequencysignals in response to the voltage, wherein the input radiofrequencysignals being indicative of impedance of the organ.

According to still further features in the described preferredembodiments the system further comprises at least one sensor for sensingthe voltage, the at least one sensor being constructed and designed forgenerating signals having a magnitude which is a function of blood flowin, from or to the organ.

According to still further features in the described preferredembodiments the electronic circuitry comprises a differentiator forperforming at least one time-differentiation, to provide a respectivederivative of the impedance between the first and the second locations.

According to still further features in the described preferredembodiments the system further comprises a display device for displayingthe blood flow.

According to another aspect of the present invention there is providedan electrode for transmitting and receiving signals of an internal organof a subject, comprising at least one elongated conducting materialconstructed and designed to wind at least a portion of an external organof the subject, so as to have a substantial constant sensitivity to thesignals, irrespectively of an orientation of the electrode on theexternal organ.

According to further features in preferred embodiments of the inventiondescribed below, the electrode further comprises an attaching material.

According to yet another aspect of the present invention there isprovided an apparatus for determining blood flow in an organ of asubject, the apparatus having a radiofrequency measuring unit, theradiofrequency measuring unit is capable of transmitting outputradiofrequency signals to the organ and receiving input radiofrequencysignals of the organ, the apparatus comprising: (a) a mixer,electrically communicating with the radiofrequency measuring unit, formixing the output radiofrequency signals and the input radiofrequencysignals, so as to provide a mixed radiofrequency signal being indicativeof the blood flow; and (b) electronic circuitry, constructed anddesigned to filter out a portion of the mixed radiofrequency signal soas to substantially increase a signal-to-noise ratio of a remainingportion of the mixed radiofrequency signal.

According to further features in preferred embodiments of the inventiondescribed below, the mixer is operable to provide a radiofrequency sumand a radiofrequency difference.

According to still further features in the described preferredembodiments the electronic circuitry comprises a low pass filter forfiltering out the radiofrequency sum.

According to still further features in the described preferredembodiments the electronic circuitry comprises an analog amplificationcircuit for amplifying the remaining portion of the mixed radiofrequencysignal.

According to still further features in the described preferredembodiments the electronic circuitry comprises a digitizer fordigitizing the remaining portion of the mixed radiofrequency signal.

According to still further features in the described preferredembodiments the electronic circuitry comprises a differentiator forperforming at least one time-differentiation, to provide a respectivederivative of an impedance between a first location and a secondlocation of the body of the subject.

According to still further features in the described preferredembodiments the differentiator is selected from the group consisting ofa digital differentiator and an analog differentiator.

According to still another aspect of the present invention there isprovided a method of measuring blood flow in an organ of a subject, themethod comprising: generating output radiofrequency signals;transmitting the output radiofrequency signals to the organ and sensinginput radiofrequency signals of the organ; mixing the outputradiofrequency signals and the input radiofrequency signals, so as toprovide a mixed radiofrequency signal being indicative of the blood flowand filtering out a portion of the mixed radiofrequency signal so as tosubstantially increase a signal-to-noise ratio of a remaining portion ofthe mixed radiofrequency signal, thereby measuring the blood flow.

According to further features in preferred embodiments of the inventiondescribed below, the mixing comprises providing a radiofrequency sum anda radiofrequency difference.

According to still further features in the described preferredembodiments the filtering the portion of the mixed radiofrequency signalis by a low pass filter constructed and designed for filtering out theradiofrequency sum.

According to still further features in the described preferredembodiments the method further comprises analogically amplifying theremaining portion of the mixed radiofrequency signal.

According to still further features in the described preferredembodiments the method further comprises digitizing the remainingportion of the mixed radiofrequency signal.

According to still further features in the described preferredembodiments the electronic circuitry is designed and constructed so asto minimize sensitivity of the input radiofrequency signals to impedancedifferences between the plurality of electrodes and the organ of thesubject.

According to still further features in the described preferredembodiments the electronic circuitry comprises at least one differentialamplifier characterized by an impedance being substantially larger thanthe impedance differences between the plurality of electrodes and theorgan of the subject.

According to still further features in the described preferredembodiments the method further comprises calculating at least onequantity using the remaining portion of the mixed radiofrequency signal,the at least one quantity being selected from the group consisting of astroke volume, a cardiac output and a brain intra luminal blood volumeand an artery blood flow rate.

According to still further features in the described preferredembodiments the artery blood flow rate is selected from the groupconsisting of an external carotid blood flow rate, an internal carotidblood flow rate, an ulnar blood flow rate, a radial blood flow rate, abrachial blood flow rate, a common iliac blood flow rate, an externaliliac blood flow rate, a posterior tibial blood flow rate, an anteriortibial blood flow rate, a peroneal blood flow rate, a lateral plantarblood flow rate, a medial plantar blood flow rate, a deep plantar bloodflow rate.

According to still further features in the described preferredembodiments the method further comprises controlling a heart rate of thesubject in accordance with a value of the at least one quantity.

According to still further features in the described preferredembodiments the controlling a heart rate of the subject is by apacemaker.

According to still further features in the described preferredembodiments the method further comprises using a value of the at leastone quantity for selecting an amount and a type of drugs andadministrating the amount and the type of drugs to the subject.

According to still further features in the described preferredembodiments the method further comprises providing a site of surgicalaccess to a portion of a heart of a subject and maintaining thereduction of cardiac expansion of the portion of the heart a substantialamount of time so as to increasing the cardiac output.

According to still further features in the described preferredembodiments the transmitting the output radiofrequency signals to theorgan and sensing the input radiofrequency signals of the organ is byconnecting a plurality of electrodes to the skin of the subject.

According to still further features in the described preferredembodiments at least a portion of the plurality of electrodes aredesigned and constructed to so as to have a substantial constantsensitivity to electrical signals transmitted through the electrodes,irrespectively of an orientation of the electrodes on the subject.

According to still further features in the described preferredembodiments at least a portion of the plurality of electrodes comprisesan attaching material.

According to still further features in the described preferredembodiments a number of the plurality of electrodes is selected so as tosubstantially decouple the input radiofrequency signals from at leastone effect selected from the group consisting of a posture changeseffect, a respiration effect and a motion effect.

According to still further features in the described preferredembodiments the plurality of electrodes comprises two electrodes.

According to still further features in the described preferredembodiments the plurality of electrodes comprises three electrodes.

According to still further features in the described preferredembodiments the plurality of electrodes comprises four electrodes.

According to still further features in the described preferredembodiments the connecting the plurality of electrodes is done so as tohave a substantial constant sensitivity to electrical signalstransmitted through the electrodes, irrespectively of an orientation ofthe electrodes on the subject.

According to still further features in the described preferredembodiments at least a portion of the plurality of electrodes comprisesat least one elongated conducting material constructed and designed towind at least a portion of an external organ of the subject, so as tohave a substantial constant sensitivity to electrical signalstransmitted through the electrodes, irrespectively of an orientation ofthe electrodes on the external organ.

According to still further features in the described preferredembodiments the external organ is selected from the group consisting ofa chest, a hip, a thigh, a neck, a head, an arm, a forearm, an abdomen,a gluteus, a leg and a foot.

According to still further features in the described preferredembodiments the method further comprises detecting a voltage between afirst location and a second location of the subject and generating theinput radiofrequency signals in response to the voltage, wherein theinput radiofrequency signals being indicative of impedance of the organ.

According to still further features in the described preferredembodiments the method further comprises performing at least onetime-differentiation thereby providing a respective derivative of theimpedance between the first and the second locations.

According to still further features in the described preferredembodiments the derivative is selected from the group consisting of afirst derivative and a second derivative.

According to still further features in the described preferredembodiments the performing the time-differentiation is effected by aprocedure selected from the group consisting of a digitaldifferentiation and an analog differentiation.

According to still further features in the described preferredembodiments the method further comprises displaying the blood flow usinga display device.

According to still further features in the described preferredembodiments the display device is capable of displaying the blood flowas a function of time.

According to still further features in the described preferredembodiments the signal-to-noise ratio is increased by at least 10 dB.

According to still further features in the described preferredembodiments the signal-to-noise ratio is increased by at least 20 dB.

The present invention successfully addresses the shortcomings of thepresently known configurations by providing a system, method andapparatus for measuring blood flow, far exceeding prior arttechnologies.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the patentspecification, including definitions, will control. In addition, thematerials, methods and examples are illustrative only and not intendedto be limiting.

Implementation of the method and system of the present inventioninvolves performing or completing selected tasks or steps manually,automatically, or a combination thereof. Moreover, according to actualinstrumentation and equipment of preferred embodiments of the method andsystem of the present invention, several selected steps could beimplemented by hardware or by software on any operating system of anyfirmware or a combination thereof. For example, as hardware, selectedsteps of the invention could be implemented as a chip or a circuit. Assoftware, selected steps of the invention could be implemented as aplurality of software instructions being executed by a computer usingany suitable operating system. In any case, selected steps of the methodand system of the invention could be described as being performed by adata processor, such as a computing platform for executing a pluralityof instructions.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only and are presented inthe cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

In the drawings:

FIG. 1 is a schematic illustration of a conventional bioimpedancesystem, according to prior art teachings;

FIG. 2 is a schematic illustration of a system for measuring blood flowin an organ of a subject, according to a preferred embodiment of thepresent invention;

FIG. 3 is a schematic illustration of electronic circuitry for filteringout a portion of a signal so that a remaining portion of the signal ischaracterized by a substantially increased signal-to-noise ratio;

FIGS. 4 a-h are schematic illustrations of electrodes (c, d, g and h)and the respective positions to which the electrodes are attached (a, b,e and f), according to a preferred embodiment of the present invention;

FIG. 5 is a schematic illustration of an apparatus for determining bloodflow in an organ of a subject, according to a preferred embodiment ofthe present invention;

FIG. 6 is a flowchart of a method of measuring blood flow in an organ ofa subject, according to a preferred embodiment of the present invention;

FIG. 7 a is a block diagram of a printed circuit board for measuringblood flow, using three electrodes;

FIG. 7 b is a block diagram of a printed circuit board for measuringblood flow, using two electrodes;

FIG. 7 c is a block diagram of a printed circuit board for measuringblood flow, using four electrodes;

FIG. 7 d is a block diagram of an analog amplification circuit foramplifying the radiofrequency signal;

FIGS. 8 a-b show monitoring results of the change in the bioimpedanceand its measured derivative, obtained using a prototype system withthree electrodes built according to a preferred embodiment of thepresent invention, for the purpose of determining stroke volume andcardiac output;

FIG. 8 c shows monitoring results of the ECG signal, change in thebioimpedance, its first derivative and its second derivative, obtainedusing a conventional (prior art) system;

FIGS. 9 a-b show monitoring results of the change in the bioimpedanceand its measured derivative obtained using the prototype system with twoelectrodes, built for the purpose of measuring brain intra luminal bloodvolume change and flow rate.

FIG. 10 shows monitoring results of the change in the bioimpedance andits measured derivative, obtained using a prototype system with fourelectrodes built according to a preferred embodiment of the presentinvention, for the purpose of determining stroke volume and cardiacoutput; and

FIG. 11 show monitoring results of the change in the bioimpedance andits measured derivative obtained using the prototype system with fourelectrodes, for the purpose of measuring brain intra luminal bloodvolume change and flow rate.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of a system, method and apparatus for measuringblood flow in an organ of a subject, which can be used for determiningmany blood-flow related parameters for the purpose of medical diagnosisand/or treatment. Specifically, the present invention can be used fordetermining stroke volume, cardiac output, brain intra luminal bloodvolume and blood flow in other arteries of the body such as, but notlimited to, arteries in the chest, hip, thigh, neck, head, arm, forearm,abdomen, gluteus, leg and foot The present invention is further ofelectrodes, which may be used for the purpose of sensing electricalsignals of the body of the subject.

The electrodes can be used in combination with the system and apparatusof the present invention as well as in combination with other medicaldevices. In addition, the electrodes of the present invention can beused for other medical procedures.

For purposes of better understanding the present invention, asillustrated in FIGS. 2-9 b of the drawings, reference is first made tothe construction and operation of a conventional (i.e., prior art)system for determining blood flow as illustrated in FIG. 1.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

Referring now to the drawings, FIG. 1 illustrates the conventionalsystem, generally referred to herein as system 10, which includes aradiofrequency generator 12 for generating a periodic high frequencycurrent output in response to a periodic control input signal. System 10further includes output spot electrodes 14 for carrying current outputfrom radiofrequency generator 12. Electrodes 14 are connected tolocations of a human body 13 above and below the heart. Shown in FIG. 1are two output spot electrodes, connected to two pairs of locations, afirst pair A and a second pair D, hence form a tetrapolar array ofelectrodes. Current, generated by radiofrequency generator 12, flowsbetween location pairs A and D and causes a voltage drop on the segmentA-D, due to the impedance of body 13.

System 10 further includes an electrical bioimpedance detector 15 andfour additional electrodes for detecting a voltage signal, between twoadditional location pairs designated B and C, located respectively inproximity to pairs A and D and, similarly to electrodes 14, form atetrapolar array of electrodes. Bioimpedance detector 15 is connected tobody 13 through two input spot electrodes 17. Detector 15 generates anoutput signal indicative of the impedance of segment B-C, in response tothe voltage signal received by electrodes 17.

The voltage signal is proportional to the magnitude of the periodiccurrent and also proportional to the electrical bioimpedance of thetissue between the pairs A and D (or pairs B and C).

The radiofrequency generator typically generates a high frequencycurrent a few milliamperes Root Mean Square in magnitude and a few tensof lilohertz in frequency.

The amplitude of the voltage signal is modulated by changes inconductivity in the body segment. In the thorax, such changes are due tochanges in the volume of blood within the thorax and by orientation oferythrocytes as a function of blood flow velocity in major arteries. Thevoltage signal modulation envelope is a superimposed sum of conductivitychanges caused by changes in posture, respiration, cardiac cycle, motionartifacts and electrical noise.

The determination of the blood flow is thus by measuring the impedancechange, ΔZ and calculating the blood flow therefrom. Typically, however,the value of the impedance change, ΔZ, is smaller than the value of theimpedance, Z, by 2-4 orders of magnitude, thus affecting the quality ofthe measurement of ΔZ, in terms of signal-to-noise ratio. The noisecontent of the received signal is reduced by the use of one or more bandpass filters, filtering out frequencies below a low threshold and abovea high threshold. Nevertheless, the efficiency of known band passfilters is insufficient and the resulting signal still has a substantialamount of the noise content folded therein.

While conceiving the present invention it has been hypothesized andwhile educing the present invention to practice it has been realizedthat the signal-to-noise ratio may be considerably increased bycombining radiofrequency techniques with analog electronics.

Hence, according to one aspect of the present invention there isprovided a system for measuring blood flow in an organ of a subject,generally referred to herein as system 20.

Reference is now made to FIG. 2, which is a schematic illustration ofsystem 20. System 20 comprises a radiofrequency generator 22, forgenerating output radiofrequency signals. Generator 22 may be embodiedas any radiofrequency generator, such as, but not limited to,radiofrequency generator 12 of system 10. System 20 further comprises aplurality of electrodes 25, which are connected to the skin of subject21. Electrodes 25 transmit output radiofrequency signals 24, generatedby generator 22 and sense input radiofrequency signals 26 originatedfrom the organ of subject 21.

According to a preferred embodiment of the present invention system 20may further comprise a bioimpedance detector 29 for detecting a voltagedrop on a portion of the body of subject 21 defined by the positions ofelectrodes 25. In response to the detected voltage, detector 29preferably generates signals 26 which are indicative of impedance of therespective portion of the body.

System 20 further comprise a mixer 28, electrically communicating withgenerator 22 and at least a portion of electrodes 25, for mixing signals24 and signals 26, so as to provide a mixed radiofrequency signal 30being indicative of the blood flow. Signals 24 and 26 may be inputtedinto mixer 28 through more than one channel, depending on optionalanalog processing procedures (e.g., amplification) which may beperformed prior to the mixing.

For example, in one embodiment, both signals 24 and 26 may be inputtedinto mixer 28 directly from the terminals that are used for transmittingthe signals to and from electrodes 25. In another embodiment, signal 26may be inputted via an additional unit 27, which is designed forprocessing signal 26. In an additional embodiment, signal 24 may beinputted from generator 22 where certain analog processing proceduresare performed prior to the mixing.

Mixer 28 may be any known radiofrequency mixer, such as, but not limitedto, double-balanced radiofrequency mixer and unbalanced radiofrequencymixer.

According to a preferred embodiment of the present invention, mixedradiofrequency signal 30 is composed of a plurality of radiofrequencysignals, which may be, in one embodiment, a radiofrequency sum and aradiofrequency difference. A sum and a difference may be achieved, e.g.,by selecting mixer 28 so that signals 24 and signals 26 are multipliedthereby. Since a multiplication between two frequencies is equivalent toa frequency sum and a frequency difference, mixer 28 outputs a signalwhich is composed of the desired radiofrequency sum and radiofrequencydifference.

One ordinarily skilled in the art would appreciate that the advantage inthe production of a radiofrequency sum and a radiofrequency differenceis that whereas the radiofrequency sum includes both the signal, whichis indicative of the blood flow and a considerable amount of electricalnoise, the radiofrequency difference is approximately noise-free.

Thus, the present invention provides an efficient technique forminimizing the electrical noise being associated with such an involvedmeasurement in which the effect of interest is smaller than the measuredquantity by about 2-4 orders of magnitude

System 20 further comprises electronic circuitry 32, constructed anddesigned to filter out a portion of signal 30 so that a remainingportion 31 of signal 30 is characterized by a substantially increasedsignal-to-noise ratio.

Reference is now made to FIG. 3, which is a schematic illustration ofcircuitry 32. According to a preferred embodiment of the presentinvention circuitry 32 comprises a low pass filter 34 to filter out thehigh frequency content of signal 30.

Low pass filter 34 is particularly useful in the embodiment in whichmixer 28 outputs a sum and a difference, where low pass filter filtersout the radiofrequency sum and leaves the radiofrequency difference,which, as stated, is approximately noise-free.

Low pass 34 filter may be designed and constructed in accordance withthe radiofrequency difference of a particular system which employssystem 20. A judicious design of filter 34 substantially reduces thenoise content of remaining portion 31. In a conventional bioimpedancesystem, for example, a substantial amount of the noise of the receivedsignal is folded into the remaining signal, which is thus characterizedby a bandwidth of about 2 kilohertz. It has been found by the inventorsof the present invention that by including output radiofrequency signal24 and by mixing it with input radiofrequency signal 26, the noise inthe resulting signal is characterized by a bandwidth that is at leastone order of magnitude below the noise bandwidth of conventionalsystems.

According to a preferred embodiment of the present invention, mixer 28and circuitry 32 are constructed and designed for increasing thesignal-to-noise ratio by at least 20 dB, more preferably by 25 dB, mostpreferably by 30 dB.

Circuitry 32 preferably comprises an analog amplification circuit 36 foramplifying remaining portion 31 of signal 30. The construction anddesign of analog amplification circuit 36 is not limited, providedcircuit 36 is capable of amplifying signal 31. A non limiting example ofamplification circuit 36 is further detailed herein below in theExamples section that follows.

According to a preferred embodiment of the present invention circuitry32 further comprises a digitizer 38 for digitizing signal 31. Thedigitization of signal 31 is useful for further digital processing ofthe digitized signal, e.g., by a microprocessor.

Additionally and preferably, circuitry comprises a differentiator 40(either a digital differentiator or an analog differentiator) forperforming at least one time-differentiation of the measured impedanceto obtain a respective derivative (e.g., a first derivative, a secondderivative, etc.) of the impedance. Differentiator 40 may comprise anyknown electronic functionality (e.g., a chip) that is capable ofperforming analog or digital differentiation. The time-derivative of theimpedance is useful, for example, for measuring stroke volume or cardiacoutput, as further detailed hereinafter.

Referring now again to FIG. 2, according to a preferred embodiment ofthe present invention system 20 further comprises a data processor 42for calculating at least one quantity using signal 31. Many blood-volumerelated quantities may be calculated, such as, but not limited to, astroke volume, a cardiac output and a brain intra luminal blood volume.System 20 may further comprise a display device 49 for displaying theblood flow and other information, preferably as a function of time.

Following is a description of a calculation procedure of the strokevolume and the cardiac output, using the time-derivative of theimpedance, dZ/dt.

The impedance change, ΔZ, is proportional to the time-derivative of theimpedance, Z. Thus, by performing the time-differentiation of theimpedance, system 20 provides a useful parameter from which theimpedance change, ΔZ and subsequently the stroke volume or the cardiacoutput may be determined. More specifically, the stroke volume is givenby R (L/Z₀)² TdZ/dt, where R is resistivity of the blood, L is thedistance between the electrodes, T is the systolic ejection time and Z₀is the non-varying impedance. Knowing the stroke volume, the cardiacoutput is calculated by multiplying the stroke volume by the heart rateof the subject.

The blood flow determination provided by system 20 may be used both fordiagnostic and for treatment Hence, according to a preferred embodimentof the present invention, system 20 may further comprise a pacemaker 44,communicating with data processor 42. In this embodiment, data processor42 is preferably programmed to electronically control pacemaker 44 inaccordance with the calculated quantity. For example, in one embodiment,data processor 42 calculates the cardiac output and sends signals topacemaker 44 which controls, substantially in real-time, the heart rateof subject 21, so as to improve the cardiac output.

Additionally or alternatively, system 20 may also comprise a cardiacassist device 48, preferably constructed and design for increasing thecardiac output. Cardiac assist devices are known in the art andtypically comprise a reinforcing member which restricts an expansion ofa portion of the heart tissue, so that the cardiac output is increased.In this embodiment, data processor 42 is preferably programmed toelectronically control device 48 in accordance with the calculatedcardiac output, so that both the determination and the improvement ofthe cardiac output are automatically performed by system 20.

According to a preferred embodiment of the present invention system 20may comprise a drug administrating device 46, communicating with dataprocessor 42. Device 46 serves for administrating drugs to subject 21.In this embodiment, data processor 42 is preferably programmed toelectronically control device 46, in accordance with the value of thecalculated quantity. For example, if the calculated quantity is thebrain intra luminal blood volume, then depending on the value of theblood volume, data processor 42 sends signal to device 46 and therebycontrols the amount and/or type of medications administered to subject21.

The number of electrodes which are connected to subject 21 is preferablyselected so as to substantially decouple the input radiofrequencysignals from undesired effects, such as, but not limited to, a posturechanges effect, a respiration effect, a motion effect and the like.

For any number of electrodes which are used, according to a preferredembodiment of the present invention, at least a portion of theelectrodes are designed and constructed to so as to have a substantialconstant sensitivity to electrical signals transmitted throughelectrodes, irrespectively of an orientation of the electrodes on thesubject.

Reference is now made to FIGS. 4 a-h, which are schematic illustrationsof electrodes 25 (FIGS. 4 c, 4 d, 4 g and 4 h) and the respectivepositions to which electrodes 25 are attached (FIGS. 4 a, 4 b, 4 e and 4f), according to a preferred embodiment of the present invention. FIGS.4 c and 4 g shows the inner side of electrode 25 and FIGS. 4 d and 4 hshows the outer side of electrode 25.

Hence, electrodes 25 preferably comprise at least one elongatedconducting material 50 constructed and designed to wind at least aportion of an external organ, which may be, for example, a chest, a hip,a thigh, a neck, a head, an arm, a forearm, an abdomen, a gluteus, aleg, a foot and the like. Optionally, electrode 25 may also comprise anattaching material 52 (e.g., velcro, glue and the like) for facilitatingthe attachment of electrode 25 to subject 21.

It is recognized that conventional spot electrodes, which are used,e.g., in bioimpedance systems (see, e.g., FIG. 1), are sensitive to theparticular position to which the electrodes are attached. Thissensitivity is particularly disadvantageous in bioimpedance systemswhere the signal-to-noise ratio is intrinsically small and thefluctuations caused by such artifacts may be comparable to the entireeffect which is to be measured. It is further recognized that theproblems associated with the sensitivity to small displacements areaggravated when the number of spot electrodes increases. Specifically,with a tetrapolar array of FIG. 1, there are eight spot electrodes eachof which contribute to the sensitivity to small displacements, henceincreasing the uncertainty of the final measurement.

The advantage of the use of electrodes 25, according to the presentlypreferred embodiment of the invention, is that the signal which isreceived from the body of subject 21 does not depend on smalldisplacements of the electrodes. In addition, as further detailed hereinbelow, the number of electrodes which are used is substantially smallerthan the number which is used in conventional systems. It will beappreciated that smaller number of electrodes (i) reduces theuncertainty factor; (ii) is more easy to attach; and (iii) morecomfortable to the patient.

Referring to FIG. 4 a, in one embodiment, one electrode is attached tothe neck of subject 21 and two electrodes are attached below the heart.This embodiment may be used, for example, for measuring and determiningstroke volume and cardiac output. It is it be understood, however, thatother configurations are not excluded for the purpose of determiningstroke volume and cardiac output. Specifically, two electrodes may beused. Nevertheless, it was found by the inventors of the presentinvention, that the motion effects with the use of three electrodes wereless pronounced than with the use of two electrodes. The preferredelectrodes to be used in this embodiment are shown in FIGS. 4 c (innerside) and 4 d (outer side).

Referring to FIG. 4 b, in another embodiment, two electrodes areattached to the neck of subject 21 and two electrodes are attached belowthe heart. This embodiment may be used, for example, for measuring anddetermining stroke volume and cardiac output. As demonstrated in theExamples section that follows, the quality of the results issignificantly enhanced with the use of four electrodes. The preferredelectrodes to be used in this embodiment are shown in FIGS. 4 c (innerside) and 4 d (outer side).

Referring to FIGS. 4 e-h, in an additional embodiment, two electrodesformed on a single elongated strip may be used for the purpose ofdetermining brain intra luminal blood volume. Specifically, as shown inFIG. 4 e, a single strip (thus, two electrodes) may be wound around theforehead of subject 21, or alternatively and preferably, two strips(thus, four electrodes) may be adjacently wound around the forehead ofsubject 21.

It is to be understood that any number of electrodes or connectionconfigurations are not excluded from the present invention. For example,the electrodes shown in FIGS. 4 c-d, the electrodes shown in FIGS. 4 g-hor any other electrodes may be used, in any combination, for measuringblood flow in any artery of the body, such as, but not limited to, theexternal carotid artery, the internal carotid artery, the ulnar artery,the radial artery, the brachial artery, the common iliac artery, theexternal iliac artery, the posterior tibial artery, the anterior tibialartery, the peroneal artery, the lateral plantar artery, the medialplantar artery and the deep plantar artery.

According to another aspect of the present invention there is providedan apparatus for determining blood flow in an organ of a subject,generally referred to herein as apparatus 60. As further detailed below,apparatus 60 enjoys the property of an enhanced signal-to-noise ratioand, as such, apparatus 60 may be used in combination with anybiopedance system, e.g., system 20.

Reference is now made to FIG. 5, which is a schematic illustration ofapparatus 60. Apparatus 60 has a radiofrequency measuring unit 22,capable of transmitting output radiofrequency signals 24 to the organand receiving input radiofrequency signals of the organ 26.Radiofrequency measuring unit 22 may be any suitable unit which isknown, per se, for example, unit 22 may comprise radiofrequencygenerator 22 and bioimpedance detector 29 as further detailed hereinabove. Unit 22 is preferably capable of performing analog processing ofthe signals (e.g., amplification). According to a preferred embodimentof the present invention, unit 22 transmits and receives signals througha plurality of electrodes as further detailed herein above.

Apparatus 60 further comprises mixer 28 for mixing signals 24 andsignals 26, to provide a mixed radiofrequency signal 30 as furtherdetailed herein above. As illustrated in FIG. 5, signals 24 and 26 maybe inputted into mixer 28 either directly from the terminals, which areused for transmitting the signals to and from the organ, or via unit 22.

Apparatus 60 further comprises electronic circuitry 32 for filtering outa portion of signal 30 so that a remaining portion 31 of signal 30 ischaracterized by a substantially increased signal-to-noise ratio, asdetailed above.

According to an additional aspect of the present invention there isprovided a method of measuring blood flow in an organ of a subject, themethod comprising the following steps, which are illustrated in theflowchart of FIG. 6. Hence, in a first step, designated by Block 72,output radiofrequency signals are generated, e.g., by a radiofrequencygenerator. In a second step, designated by Block 74, the outputradiofrequency signals are transmitting to the organ and inputradiofrequency signals are sensed of the organ, e.g., by an array ofelectrodes. In a third step, designated by Block 76, the outputradiofrequency signals and the input radiofrequency signals are mixed,so as to provide a mixed radiofrequency signal being indicative of theblood flow, as further detailed herein above. In a fourth step,designated by Block 78, a portion of the mixed radiofrequency signal isfiltered out so as to substantially increase the signal-to-noise ratioof a remaining portion thereof as further detailed herein above.

According to a preferred embodiment of the present invention, the methodmay further comprise the following optional steps, where each optionalstep may be performed independently of the other optional steps in anycombination or order. Hence, in one optional step, designated by Block80 the remaining portion of the mixed radiofrequency signal isanalogically amplified; in another optional step, designated by Block82, the remaining portion of mixed radiofrequency signal is digitized;in an additional optional step, designated by Block 84, at least onequantity (e.g., a stroke volume, a cardiac output and a brain intraluminal blood volume) is calculated; in still an additional step,designated by Block 86, at least one time-differentiation is performed,as further detailed herein above.

Following are technical preferred values which may be used for selectivesteps and parts of the embodiments described above.

As used herein the term “about” refers to ±10%.

The output radiofrequency signals are preferably from about 10 KHz toabout 200 KHz in frequency and from about 10 mV to about 50 mV inmagnitude; the input radiofrequency signals are preferably about 70 KHzin frequency and about 20 mV in magnitude; a typical impedance which canbe measured by the present embodiments is from about 25 Ohms to about 35Ohms; the resulting signal-to-noise ratio of the present embodiments isat least 40 dB; low pass filter 34 is preferably characterized by acutoff frequency of about 35 Hz and digitizer 38 preferably samples thesignals at a rate of about 1000 samples per second.

Additional objects, advantages and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated herein above and as claimed in theclaims section below finds experimental support in the followingexamples.

EXAMPLES

Reference is now made to the following examples, which, together withthe above descriptions, illustrate the invention in a non limitingfashion.

A prototype of a system for measuring blood flow in an organ of asubject according to the above description was constructed.

The prototype system includes:

(a) a self made radiofrequency generator generating outputradiofrequency signals, 70 Khz in frequency and 20 mV in magnitude;

(b) a plurality of electrodes, as described in FIGS. 4 b, 4 c, 4 e and 4f, and

(c) a double balanced mixer, purchased from Mini-Circuits, used forproviding a radiofrequency sum and a radiofrequency difference, asdetailed above.

The prototype system further includes electronic circuitry formed in aprinted circuit board. Several electronic circuitries were designed andmanufactured, so as to investigate the correlation between the qualityof the results, the design of the electronic circuitry and the number ofelectrodes. The various electronic circuitries are schematicallyillustrated in FIGS. 7 a-d.

FIG. 7 a shows a block diagram of electronic circuitry to be used withthree electrodes (see results of cardiac-output measurements in Example1, below). The electrodes leads are designated in FIG. 7 a by E₁, E₂ andI₁, where the output radiofrequency signals, generated by theradiofrequency generator (designated OSC), are outputted through E₁ andE₂ and the input radiofrequency signals, as measured of the body areinputted through I₁.

The input signals and are channeled through a differential amplifier G₁,a band pass filter BPF and a differential amplifier G₂. Similarly, theinput signals and are channeled through a differential amplifier G₃, aband pass filter BPF and a differential amplifier G₄. Once amplified andfiltered both input and output signals are mixed by mixer DMB, to form,as stated, a frequency sum and a frequency difference. A low pass filterLPF filters out the frequency sum and the resulting signal (carrying thefrequency difference) is further amplified by additional differentialamplifiers G₅, G₆ and G₇. Once amplified, the signal is digitized by ananalog to digital digitizer and passed, via a USB communicationinterface to a processing and display unit.

FIG. 7 b shows a block diagram of electronic circuitry to be used withtwo electrodes of brain intra-luminal blood volume measurements inExample 2, below). As there are only two electrodes E₂ and I₁ arecombined to a single lead I₁.

Thus, the input signals and are channeled through a differentialamplifier G₁, a band pass filter BPF and a differential amplifier G₂.The input signals and are channeled through a differential amplifier G₂and a band pass filter BPF (no additional amplification is performedprior to mixing in this configuration). Once amplified and filtered bothinput and output signals are mixed by mixer DMB, to form the frequencysum and difference. The low pass filter LPF filters out the frequencysum and the resulting signal is further amplified by additionaldifferential amplifiers G₄, G₅ and G₆. As in the case of threeelectrodes, the signal is digitized by an analog to digital digitizerand passed, via a USB communication interface to a processing anddisplay unit.

FIG. 7 c shows a block diagram of electronic circuitry to be used withfour electrodes (see results of cardiac-output measurements in Example 3and brain intra-luminal blood volume measurement in Example 4, below).The four leads, designated E₁, E₂, I₁ and I₂, where the outputradiofrequency signals, generated by radiofrequency generator OSC, areoutputted through E₁ and E₂ and the input radiofrequency signals, asmeasured of the body are inputted through I₁ and I₂. In addition, thefour leads, E₁, E₂, I₁ and I₂ are connected to the body throughcapacitors designated C₁, C₂, C₃ and C₄.

The principles of the circuitry of FIG. 7 c are similar to theprinciples of the circuitry of FIG. 7 a with three electrodes. Theadvantage of the circuitry of FIG. 7 c is that by using both input leadsI₁ and I₂ (as opposed to one input lead I₁ of FIG. 7 a), effects ofimpedance differences between the electrodes and the body can beminimized. Specifically, the influence of the voltage drop I₁ and I₂ iscontrolled by the characteristic impedance of the differential amplifierG₃, which is selected to be sufficiently large so that any impedancechanges due to the contact between the body and the electrode isnegligible, compared to the impedance of G₃.

FIG. 7 d shows a block diagram of the analog amplification circuit,which was used to amplify the radiofrequency signal after the low passfiltering in which the radiofrequency sum was filtered out.

Example 1 Measurement of Stroke Volume and Cardiac Output Using ThreeElectrodes

Three electrodes were connected to a human subject, as shown in FIG. 4 aThe bioimpedance was measured and was used for determining andmonitoring (i) stroke volume; and (ii) cardiac output.

FIGS. 8 a-b shows the monitoring results obtained using the prototypesystem (using the circuitry of FIG. 7 a) on a time scale of 250 ms/div.Two waveforms are displayed in each of FIGS. 8 a-b, the change in thebioimpedance, ΔZ and its measured time derivative, d(ΔZ)/dt, denoted inthe following as dZ/dt. The waveforms shown in 8 b are in reversemagnification compared to the waveforms shown in 8 a.

For comparison, FIG. 8 c shows monitoring results obtained using aconventional system (GE/Cardiodynamic). The waveforms displayed in FIG.8 c, are, from top to bottom, the ECG signal, the change in thebioimpedance, ΔZ, its first derivative, dZ/dt and its second derivatived²Z/dt².

The improvement of the signal-to noise ratio of the present invention(FIGS. 8 a-b) over the conventional system (FIG. 8 c) is vivid. In theprototype system the signal-to-noise ratio was 50 dB, whereas in theconventional system the signal-to-noise ratio was 20 dB.

Example 2 Measurement of Brain Intra Luminal Blood Volume Change andFlow Rate Using Two Electrodes

Two electrodes were connected to a human subject, as shown in FIG. 4 e.The bioimpedance was measured and was used for determining andmonitoring brain intra luminal blood volume change and flow rate.

FIGS. 9 a-b show the monitoring results obtained using the prototypesystem (using the circuitry of FIG. 7 b) on a time scale of 250 ms/div.Two waveforms are displayed in each of FIGS. 9 a-b, the change in thebioimpedance, ΔZ and its measured derivative, dZ/dt, where in FIG. 9 b,the vertical scale for the curve of ΔZ is twice larger than therespective curve in FIG. 9 a.

As shown in FIGS. 9 a-b, a good signal-to noise ratio of 50 dB wasobtained for both quantities. The curves of the present example acquirea sharper peak, as compared to Example 1. This phenomenon is consistentwith physiological findings, according to which the resistance to bloodflow in the brain is substantially lower than the resistance in thethorax. Thus, in the brain, there is only a small delay in the responseto the change of blood flow, as compared to the thorax. The quickresponse to blood flow is manifested by the measured quantities hencethe sharp peaks in the curves of FIG. 9 a-b.

Example 3 Measurement of Stroke Volume and Cardiac Output Using FourElectrodes

Four electrodes were connected to a human subject, as shown in FIG. 4 b.The bioimpedance was measured and was used for determining andmonitoring (i) stroke volume; and (ii) cardiac output.

FIG. 10 shows the monitoring results obtained using the prototype system(using the circuitry of FIG. 7 c) on a time scale of 500 ms/div. Twowaveforms are displayed in FIG. 10, the change in the bioimpedance, ΔZand its measured time derivative, d(ΔZ)/dt, denoted in the following asdZ/dt.

Comparing FIG. 10 and FIGS. 8 a-b, the use of four electrodes (and theelectronic circuitry of FIG. 7 c) significantly improves of the qualityof the results.

Example 4 Measurement of Brain Intra Luminal Blood Volume Change andFlow Rate Using Four Electrodes

Two electrodes were connected to a human subject, as shown in FIG. 4 f.The bioimpedance was measured and was used for determining andmonitoring brain intra luminal blood volume change and flow rate.

FIG. 11 show the monitoring results obtained using the prototype system(using the circuitry of FIG. 7 c) on a time scale of 500 ms/div. Twowaveforms are displayed in FIG. 11, the change in the bioimpedance, ΔZand its measured derivative, dz/dt.

As shown in FIG. 11, a good signal-to noise ratio of 50 dB was obtainedfor both quantities. As in Example 3 above, a comparison between FIGS.11 and 9 a-b, reveal a significant improvement of the present example(four electrodes and the circuitry of FIG. 7 c) over Example 2 (twoelectrodes and the circuitry of FIG. 7 b).

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications mentioned in this specification are herein incorporated intheir entirety by reference into the specification, to the same extentas if each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated herein byreference. In addition, citation or identification of any reference inthis application shall not be construed as an admission that suchreference is available as prior art to the present invention.

What is claimed is:
 1. A system for measuring blood flow in an organ ofa subject, the system comprising: a radiofrequency generator forgenerating output radiofrequency signals; a plurality of electrodes,designed to be connectable to the skin of the subject, said electrodesbeing for transmitting said output radiofrequency signals to the organand for sensing input radiofrequency signals of the organ; a mixer,electrically communicating with said radiofrequency generator and atleast a portion of said plurality of electrodes, for mixing said outputradiofrequency signals and said input radiofrequency signals, so as toprovide a mixed radiofrequency signal having a radiofrequency sum and aradiofrequency difference and being indicative of the blood flow;electronic circuitry, constructed and designed to filter out a portionof said mixed radiofrequency signal; and a data processor forcalculating at least one quantity using a remaining portion of saidmixed radiofrequency signal, said at least one quantity being selectedfrom the group consisting of a stroke volume, a cardiac output, a brainintra luminal blood flow and an artery blood flow rate.
 2. The system ofclaim 1, wherein said electronic circuitry comprises a low pass filterfor filtering out said radiofrequency sum.
 3. The system of claim 1,wherein said electronic circuitry comprises an analog amplificationcircuit for amplifying said remaining portion of said mixedradiofrequency signal.
 4. The system of claim 1, wherein said electroniccircuitry comprises a digitizer for digitizing said remaining portion ofsaid mixed radiofrequency signal.
 5. The system of claim 1, wherein saidelectronic circuitry is designed and constructed so as to minimizesensitivity of said input radiofrequency signals to impedancedifferences between said plurality of electrodes and the organ of thesubject.
 6. The system of claim 5, wherein said electronic circuitrycomprises at least one differential amplifier characterized by animpedance being larger than said impedance differences between saidplurality of electrodes and the organ of the subject.
 7. The system ofclaim 1, wherein said artery blood flow rate is selected from the groupconsisting of an external carotid blood flow rate, an internal carotidblood flow rate, an ulnar blood flow rate, a radial blood flow rate, abrachial blood flow rate, a common iliac blood flow rate, an externaliliac blood flow rate, a posterior tibial blood flow rate, an anteriortibial blood flow rate, a peroneal blood flow rate, a lateral plantarblood flow rate, a medial plantar blood flow rate, a deep plantar bloodflow rate.
 8. The system of claim 1, further comprising a pacemaker,communicating with said data processor and operable to control a heartrate of the subject, wherein said data processor is programmed toelectronically control said pacemaker, in accordance with a value ofsaid at least one quantity.
 9. The system of claim 1, further comprisinga drug administrating device, communicating with said data processor andoperable to administrate drugs to the subject, wherein said dataprocessor is programmed to electronically control said drugadministrating device, in accordance with a value of said at least onequantity.
 10. The system of claim 1, further comprising a cardiac assistdevice, communicating with said data processor and operable to increasesaid cardiac output.
 11. The system of claim 10, wherein said cardiacassist device comprises a reinforcing member designed and configured torestrict an expansion of a portion of a heart tissue, thereby toincrease said cardiac output.
 12. The system of claim 1, wherein anumber of said plurality of electrodes is selected so as tosubstantially decouple said input radiofrequency signals from at leastone effect selected from the group consisting of a posture changeseffect, a respiration effect and a motion effect.
 13. The system ofclaim 1, wherein said plurality of electrodes comprises two electrodes.14. The system of claim 1, wherein said plurality of electrodescomprises three electrodes.
 15. The system of claim 1, wherein saidplurality of electrodes comprises four electrodes.
 16. The system ofclaim 1, wherein at least a portion of said plurality of electrodes aredesigned and constructed so as to have a substantial constantsensitivity to electrical signals transmitted through said electrodes,irrespectively of an orientation of said electrodes on the subject. 17.The system of claim 1, wherein at least a portion of said plurality ofelectrodes comprises at least one elongated conducting materialconstructed and designed to wind at least a portion of an external organof the subject, so as to have a constant sensitivity to electricalsignals transmitted through said electrodes, irrespectively of anorientation of said electrodes on said external organ.
 18. The system ofclaim 1, wherein at least a portion of said plurality of electrodescomprises an attaching material.
 19. The system of claim 18, whereinsaid external organ is selected from the group consisting of a chest, ahip, a thigh, a neck, a head, an arm, a forearm, an abdomen, a gluteus,a leg and a foot.
 20. The system of claim 1, further comprising abioimpedance detector electrically communicating with at least a portionof said plurality of electrodes for detecting a voltage between a firstlocation and a second location of the subject and for generating saidinput radiofrequency signals in response to said voltage, wherein saidinput radiofrequency signals are indicative of impedance of the organ.21. The system of claim 20, further comprising at least one sensor forsensing said voltage, said at least one sensor being constructed anddesigned for generating signals having a magnitude which is a functionof blood flow in, from or to the organ.
 22. The system of claim 20,wherein said electronic circuitry comprises a differentiator forperforming at least one time-differentiation, to provide a respectivederivative of said impedance between said first and said secondlocations.
 23. The system of claim 22, wherein said derivative isselected from the group consisting of a first derivative and a secondderivative.
 24. The system of claim 22, wherein said differentiator isselected from the group consisting of a digital differentiator and ananalog differentiator.
 25. The system of claim 1, further comprising adisplay device for displaying the blood flow.
 26. The system of claim25, wherein said display device is capable of displaying the blood flowas a function of time.
 27. The system of claim 1, wherein saidelectronic circuitry is constructed and designed to filter out saidportion of said mixed radiofrequency signal such as to increase asignal-to-noise ratio of said remaining portion by at least 10 dB. 28.The system of claim 1, wherein said electronic circuitry is constructedand designed to filter out said portion of said mixed radiofrequencysignal such as to increase a signal-to-noise ratio of said remainingportion by at least 20 dB.
 29. An apparatus for determining blood flowin an organ of a subject, the apparatus having a radiofrequencymeasuring unit, the radiofrequency measuring unit is capable oftransmitting output radiofrequency signals to the organ and receivinginput radiofrequency signals of the organ, the apparatus furthercomprising: (a) a mixer, electrically communicating with saidradiofrequency measuring unit, for mixing said output radiofrequencysignals and said input radiofrequency signals, so as to provide a mixedradiofrequency signal having radiofrequency sum and a radiofrequencydifference and being indicative of the blood flow; and (b) electroniccircuitry, constructed and designed to filter out a portion of saidmixed radiofrequency signal, wherein said electronic circuitry comprisesa differentiator for performing at least one time-differentiation, toprovide a respective derivative of an impedance between a first locationand a second location of the body of the subject.
 30. The apparatus ofclaim 29, wherein said electronic circuitry comprises a low pass filterfor filtering out said radiofrequency sum.
 31. The apparatus of claim29, wherein said electronic circuitry comprises an analog amplificationcircuit for amplifying a remaining portion of said mixed radiofrequencysignal.
 32. The apparatus of claim 29, wherein said electronic circuitrycomprises a digitizer for digitizing a remaining portion of said mixedradiofrequency signal.
 33. The apparatus of claim 29, wherein saidelectronic circuitry is designed and constructed so as to minimizesensitivity of said input radiofrequency signals to impedancedifferences between said plurality of electrodes and the organ of thesubject.
 34. The apparatus of claim 33, wherein said electroniccircuitry comprises at least one differential amplifier characterized byan impedance being substantially larger than said impedance differencesbetween said plurality of electrodes and the organ of the subject. 35.The apparatus of claim 29, wherein said derivative is selected from thegroup consisting of a first derivative and a second derivative.
 36. Theapparatus of claim 29, wherein said differentiator is selected from thegroup consisting of a digital differentiator and an analogdifferentiator.
 37. The apparatus of claim 29, wherein said electroniccircuitry is constructed and designed to filter out said portion of saidmixed radiofrequency signal such as to increase a signal-to-noise ratioof a remaining portion by at least 10 dB.
 38. The apparatus of claim 29,wherein said electronic circuitry is constructed and designed to filterout said portion of said mixed radiofrequency signal such as to increasea signal-to-noise ratio of a remaining portion by at least 20dB.
 39. Amethod of measuring blood flow in an organ of a subject, the methodcomprising: generating output radiofrequency signals; transmitting saidoutput radiofrequency signals to the organ and sensing inputradiofrequency signals of the organ; mixing said output radiofrequencysignals and said input radiofrequency signals, so as to provide a mixedradiofrequency signal having a radiofrequency sum and a radiofrequencydifference and being indicative of the blood flow; filtering out aportion of said mixed radiofrequency signal; and calculating at leastone quantity using a remaining portion of said mixed radiofrequencysignal, said at least one quantity being selected from the groupconsisting of a stroke volume, a cardiac output, a brain intra luminalblood flow and an artery blood flow rate.
 40. The method of claim 39,wherein said filtering said portion of said mixed radiofrequency signalis by a low pass filter constructed and designed for filtering out saidradiofrequency sum.
 41. The method of claim 39, further comprisinganalogically amplifying said remaining portion of said mixedradiofrequency signal.
 42. The method of claim 39, further comprisingdigitizing said remaining portion of said mixed radiofrequency signal.43. The method of claim 39, wherein said electronic circuitry isdesigned and constructed so as to minimize sensitivity of said inputradiofrequency signals to impedance differences between said pluralityof electrodes and the organ of the subject.
 44. The method of claim 43,wherein said electronic circuitry comprises at least one differentialamplifier characterized by an impedance being substantially larger thansaid impedance differences between said plurality of electrodes and theorgan of the subject.
 45. The method of claim 39, wherein said arteryblood flow rate is selected from the group consisting of an externalcarotid blood flow rate, an internal carotid blood flow rate, an ulnarblood flow rate, a radial blood flow rate, a brachial blood flow rate, acommon iliac blood flow rate, an external iliac blood flow rate, aposterior tibial blood flow rate, an anterior tibial blood flow rate, aperoneal blood flow rate, a lateral plantar blood flow rate, a medialplantar blood flow rate, a deep plantar blood flow rate.
 46. The methodof claim 39, further comprising controlling a heart rate of the subjectin accordance with a value of said at least one quantity.
 47. The methodof claim 39, wherein said controlling a heart rate of the subject is bya pacemaker.
 48. The method of claim 39, further comprising using avalue of said at least one quantity for selecting an amount and a typeof drugs and administrating said amount and said type of drugs to thesubject.
 49. The method of claim 39, further comprising providing a siteof surgical access to a portion of a heart of a subject and maintainingthe reduction of cardiac expansion of said portion of said heart asubstantial amount of time so as to increasing said cardiac output. 50.The method of claim 39, wherein said transmitting said outputradiofrequency signals to the organ and sensing said inputradiofrequency signals of the organ is by connecting a plurality ofelectrodes to the skin of the subject.
 51. The method of claim 50,wherein a number of said plurality of electrodes is selected so as tosubstantially decouple said input radiofrequency signals from at leastone effect selected from the group consisting of a posture changeseffect, a respiration effect and a motion effect.
 52. The method ofclaim 50, wherein said plurality of electrodes comprises two electrodes.53. The method of claim 50, wherein said plurality of electrodescomprises three electrodes.
 54. The method of claim 50, wherein saidplurality of electrodes comprises four electrodes.
 55. The method ofclaim 50, wherein said connecting said plurality of is done so as tohave a substantial constant sensitivity to electrical signalstransmitted through said electrodes, irrespectively of an orientation ofsaid electrodes on the subject.
 56. The method of claim 50, wherein atleast a portion of said plurality of electrodes comprises at least oneelongated conducting material constructed and designed to wind at leasta portion of an external organ of the subject, so as to have asubstantial constant sensitivity to electrical signals transmittedthrough said electrodes, irrespectively of an orientation of saidelectrodes on said external organ.
 57. The method of claim 56, whereinsaid external organ is selected from the group consisting of a chest, ahip, a thigh, a neck, a head, an arm, a forearm, an abdomen, a gluteus,a leg and a foot.
 58. The method of claim 39, further comprisingdetecting a voltage between a first location and a second location ofthe subject and generating said input radiofrequency signals in responseto said voltage, wherein said input radiofrequency signals beingindicative of impedance of the organ.
 59. The method of claim 58,further comprising performing at least one time-differentiation therebyproviding a respective derivative of said impedance between said firstand said second locations.
 60. The method of claim 59, wherein saidderivative is selected from the group consisting of a first derivativeand a second derivative.
 61. The method of claim 59, wherein saidperforming said time-differentiation is effected by a procedure selectedfrom the group consisting of a digital differentiation and an analogdifferentiation.
 62. The method of claim 39, further comprisingdisplaying the blood flow using a display device.
 63. The method ofclaim 62, wherein said display device is capable of displaying the bloodflow as a function of time.
 64. The method of claim 39, wherein saidfiltering is performed such as to increase a signal-to-noise ratio ofsaid remaining portion by at least 10dB.
 65. The method of claim 39,wherein said filtering is performed such as to increase asignal-to-noise ratio of said remaining portion by at least 20 dB.
 66. Asystem for measuring blood flow in an organ of a subject, the systemcomprising: a radiofrequency generator for generating outputradiofrequency signals; a plurality of electrodes, designed to beconnectable to the skin of the subject, said electrodes being fortransmitting said output radiofrequency signals to the organ and forsensing input radiofrequency signals of the organ; a bioimpedancedetector electrically communicating with at least a portion of saidplurality of electrodes for detecting a voltage between a first locationand a second location of the subject and for generating inputradiofrequency signals in response to said voltage, wherein said inputradiofrequency signals are indicative of impedance of the organ; amixer, electrically communicating with said radiofrequency generator andat least a portion of said plurality of electrodes, for mixing saidoutput radiofrequency signals and said input radiofrequency signals, soas to provide a mixed radiofrequency signal radiofrequency sum and aradiofrequency difference and being indicative of the blood flow; andelectronic circuitry, constructed and designed to filter out a portionof said mixed radiofrequency signal, wherein said electronic circuitrycomprises a differentiator for performing at least onetime-differentiation, to provide a respective derivative of saidimpedance between said first and said second locations.
 67. An apparatusfor determining blood flow in an organ of a subject, the apparatushaving a radiofrequency measuring unit, the radiofrequency measuringunit is capable of transmitting output radiofrequency signals to theorgan and receiving input radiofrequency signals of the organ, theapparatus further comprising: (a) a mixer, electrically communicatingwith said radiofrequency measuring unit, for mixing said outputradiofrequency signals and said input radiofrequency signals, so as toprovide a mixed radiofrequency signal having radiofrequency sum and aradiofrequency difference and being indicative of the blood flow; (b)electronic circuitry, constructed and designed to filter out a portionof said mixed radiofrequency signal; and (c) a data processor forcalculating at least one quantity using a remaining portion of saidmixed radiofrequency signal, said at least one quantity being selectedfrom the group consisting of a stroke volume, a cardiac output, a brainintra luminal blood flow and an artery blood flow rate.